Esophageal Cancer

Esophageal cancer is a devastating disease. It is the 11th most commonly diagnosed cancer and 7th most common cause of cancer death worldwide, leading to 445,000 deaths in 2022.[4] Although some patients can be cured, the treatment for esophageal cancer is protracted, diminishes quality of life, and is lethal in a significant number of cases.

The principal histologic types of esophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma. SCC is the most common histology in Eastern Europe and Asia, while adenocarcinoma is most common in North America and Western European countries.

The incidence and mortality of esophageal cancer are 2 to 3 times higher in men.[4] Adenocarcinoma is diagnosed predominantly in White men and the incidence has risen more steeply in that population. However, adenocarcinoma is gradually increasing in men of all ethnic backgrounds and also in women.[5]

Squamous cells line the entire esophagus, so SCC can occur in any part of the esophagus, but it often arises in the upper half. Adenocarcinoma typically develops in specialized intestinal metaplasia (Barrett metaplasia) that develops as a result of gastroesophageal reflux disease (GERD); thus, adenocarcinoma typically arises in the lower half of the distal esophagus and often involves the esophagogastric junction.

Treatment history and controversy

Surgery has traditionally been the treatment for esophageal carcinoma. The first successful resection was performed in 1913 by Torek.[6] In the 1930s, Ohsawa in Japan and Marshall in the United States were the first to perform successful single-stage transthoracic esophagectomies with continent reconstruction.[7, 8]

The ideal treatment for localized esophageal cancer is sometimes debated across practice cultures and subspecialties. Proponents of surgical treatment argue that resection is the only treatment modality to offer curative intent; proponents of the nonsurgical approach claim that esophagectomy has a prohibitive index of mortality and that esophageal cancer is an incurable disease.

Analysis of the National Cancer Database from 2004 to 2014 identified 18,459 patients with locally advanced esophageal cancer, including 708 who were recommended for surgery but refused it. Median survival was 32 months for patients undergoing esophagectomy, versus 21 months in patients who refused surgery (P < 0.001).[9]

Current guidelines recommend surgery—resection or esophagectomy, depending on the stage—as a standard aspect of managing esophageal cancer. Nonoperative therapy is usually reserved for patients who are not candidates for surgery because of clinical conditions or advanced disease.[10, 11, 12, 13]

The esophagus is a muscular tube that extends from the level of the 7th cervical vertebra to the 11th thoracic vertebra. The esophagus can be divided into the following anatomic parts:

• Cervical esophagus
• Thoracic esophagus
• Abdominal esophagus

The blood supply of the cervical esophagus is derived from the inferior thyroid artery, while the blood supply for the thoracic esophagus comes from the bronchial arteries and the aorta. The abdominal esophagus is supplied by branches of the left gastric artery and inferior phrenic artery.

Venous drainage of the cervical esophagus is through the inferior thyroid vein, while the thoracic esophagus drains via the azygous vein, the hemiazygous vein, and the bronchial veins. The abdominal esophagus drains through the coronary vein.

The esophagus is characterized by a rich network of lymphatic channels in the submucosa that can facilitate the longitudinal spread of neoplastic cells along the esophageal wall. Lymphatic drainage is to the following node basins:

• Cervical
• Tracheobronchial
• Mediastinal
• Gastric
• Celiac

Major risk factors for SCC include alcohol consumption and tobacco use. Most studies have shown that alcohol is the primary risk factor but smoking in combination with alcohol consumption can have a synergistic effect. 

Alcohol damages the cellular DNA by decreasing metabolic activity within the cell and therefore inhibits detoxification and promotes oxidation.[14] Alcohol is a solvent, specifically of fat-soluble compounds. Therefore, the carcinogens within tobacco are able to penetrate the esophageal epithelium more easily. 

Some of the carcinogens in tobacco include the following:

• Aromatic amines
• Nitrosamines
• Polycyclic aromatic hydrocarbons
• Aldehydes
• Phenols

Other carcinogens, such as nitrosamines found in certain salted vegetables and preserved fish, have also been implicated in esophageal SCC. The pathogenesis appears to be linked to inflammation of the squamous epithelium that leads to dysplasia and in situ malignant transformation.[15]

Adenocarcinoma of the esophagus most commonly occurs in the distal esophagus and has a distinct relationship to GERD. Untreated GERD can progress to Barrett esophagus (BE), in which the stratified squamous epithelium that normally lines the esophagus is replaced by a columnar epithelium.

The chronic reflux of gastric acid and bile at the gastroesophageal junction and the subsequent damage to the esophagus has been implicated in the pathogenesis of Barrett metaplasia. Diagnosis of Barrett esophagus can be confirmed by biopsies of the columnar mucosa during an upper endoscopy.

Barrett esophagus incidence increases with age. The disorder is uncommon in children. It is more common in men than women and more common in whites than in Asians or African Americans.[14]

The progression of Barrett metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure.[16, 17, 18] The oncosuppressor gene TP53 and various oncogenes, particularly erb-b2, have been studied as potential markers. Casson and colleagues identified mutations in the TP53 gene in patients with Barrett epithelium associated with adenocarcinoma.[19] In addition, alterations in p16 genes and cell cycle abnormalities or aneuploidy appear to be some of the most important and well-characterized molecular changes.

Obesity is another risk factor for esophageal adenocarcinoma, specifically in individuals with central fat distribution.[20] Hypertrophied adipocytes and inflammatory cells within fat deposits create an environment of low-grade inflammation and promote tumor development through the release of adipokines and cytokines. Adipocytes in the tumor microenvironment supply energy production and support tumor growth and progression.[21]

The etiology of esophageal carcinoma is thought to be related to exposure of the esophageal mucosa to noxious or toxic stimuli, resulting in a sequence of dysplasia to carcinoma in situ to carcinoma. In Western cultures, retrospective evidence has implicated cigarette smoking and chronic alcohol exposure as the most common etiologic factors for squamous cell carcinoma. High body mass index, GERD, and resultant Barrett esophagus are often the associated factors for esophageal adenocarcinoma.[22]

Certain factors can increase or decrease risk for both cancer types. A study by Steevens et al found that in current smokers, increased consumption of specific groups of vegetables and fruits were inversely associated with risk for esophageal SCC and adenocarcinoma.[23]  Total vegetable consumption nonsignificantly reduced risk for both esophageal cancer types. Consumption of raw vegetables and of citrus fruits was inversely associated with risk for esophageal adenocarcinoma. The risk of both SCC and adenocarcinoma of the esophagus was increased in current smokers.[24]

Risk factors for esophageal squamous cell carcinoma

The risk factors and etiologic associations for SCC of the esophagus include the following:

• Smoking and alcohol use
• Diet
• Certain infections
• Tylosis

Smoking and alcohol use

The Netherlands Cohort Study, a prospective study in 120,852 participants, demonstrated the combined effects of smoking and alcohol consumption on risk of SCC of the esophagus.[24] In participants who drank 30 g or more of ethanol daily, the multivariable adjusted incidence rate ratio (RR) for esophageal SCC was 4.61 compared with abstainers. The RR for current smokers who consumed more than 15 g/day of ethanol was 8.05 when compared with nonsmokers who consumed less than 5 g/day of ethanol.

No associations were found between alcohol consumption and esophageal adenocarcinoma.

Dietary associations

Esophageal SCC has a wide variety of dietary associations, among them the following:  

• Foods products containing N-nitroso compounds increase the risk of esophageal SCC. ^[25]
• Toxin-producing fungi (eg, aflatoxin) induce carcinogenesis by reducing nitrates to nitroso compounds. ^[26]
• Areca nuts or betel quid (areca nuts wrapped in betel leaves) increase the risk through the release of copper, with resulting induction of collagen synthesis by fibroblasts ^[27]
• Red meat consumption increases the risk  ^[28]
• Low selenium levels increase risk, ^[29] while selenium supplementation reduces the risk. ^[30]
• Zinc deficiency ^[31]  mediates carcinogenesis by enhancing the carcinogenic effects of nitrosamines ^[32] and also leads to overexpression of cyclooxygenase (COX)-2. ^[33]
• Low dietary folate intake is associated with an increased risk of esophageal SCC. ^[34]
• Higher intake of fruits and vegetables reduces the risk of esophageal SCC. ^[35]

A variety of other factors may promote esophageal SCC. These include the following:

• Caustic stricture
• Achalasia cardia
• Prior gastrectomy 
• Use of oral bisphosphonates ^[36]
• Drinking scalding-hot liquids (hotter than 65° C [149° F])
• Poor oral hygiene
• Plummer-Vinson syndrome

A Chinese study found that risk for esophageal cancer was five times higher in individuals who drank very hot tea and drank more than 15 g of alcohol every day compared with those who drank tea less than once a week and consumed fewer than 15 g of alcohol daily (hazard ratio [HR], 5.00). Risk was doubled in those who drank very hot tea daily and smoked tobacco, compared with nonsmokers who drank tea only occasionally (HR, 2.03). The analysis included 456,155 participants aged 30 to 79 years who did not have a prior history of cancer.[37, 38]

A genome-wide association study by Wu et al identified seven susceptibility loci on chromosomes 5q11, 6p21, 10q23, 12q24, and 21q22, suggesting the involvement of multiple genetic loci and gene-environment interaction in the development of esophageal SCC.[39]  

Bisphosphonate use can result in esophagitis and has been suggested as a risk factor for esophageal carcinoma. However, a large study found no significant difference in the frequency of esophageal or gastric cancers between the bisphosphonate cohort and the control group.[40]

Infections

Human papillomavirus (HPV) infection has been recognized as a contributing factor to esophageal cancer. However, Sitas et al reported limited serologic evidence of an association between esophageal SCC and HPV in a study of more than 4000 subjects. The study could not exclude the possibility that certain HPV types may be involved in a small subset of cancers, although HPV does not appear to be an important risk factor.[41] . Helicobacter pylori infection, which can cause stomach cancer, has not been associated with esophageal cancer.

Tylosis

Tylosis is a rare autosomal dominant disease caused by a mutation in TEC (tylosis with esophageal cancer), a tumor suppressor gene located on chromosome 17q25. Tylosis is associated with hyperkeratosis of the palms and soles (see the images below) and a high rate of esophageal SCC (40% to 90% by the age of 70 years).[42] The inherited type of tylosis (Howell-Evans syndrome) has been most strongly linked to esophageal SCC.[43, 44] Surveillance by upper GI endoscopy is recommended for family members with tylosis after 20 years of age.[45]

Palmoplantar keratoderma (tylosis) of palms (A) and soles (B). Courtesy of The American Journal of Gastroenterology, Nature Publishing Group.

Risk factors for adenocarcinoma

The principal risk factors and etiologic associations for esophageal adenocarcinoma include the following:

• GERD
• Obesity and metabolic syndrome

Gastroesophageal reflux disease

GERD is the most common predisposing factor for adenocarcinoma of the esophagus. Adenocarcinoma may represent the last event of a sequence that starts with irritation caused by the reflux of acid and bile and progresses to specialized intestinal (Barrett) metaplasia, low-grade dysplasia, high-grade dysplasia, and finally adenocarcinoma see the image below). Approximately 10%-15% of patients who undergo endoscopy for evaluation of GERD symptoms are found to have Barrett epithelium.

Esophageal cancer. Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.

In 1952, Morson and Belcher published the first description of a patient with adenocarcinoma of the esophagus arising in a columnar epithelium with goblet cells.[46] In 1975, Naef et al emphasized the malignant potential of Barrett esophagus.[47]

The risk of adenocarcinoma in patients with Barrett metaplasia has been estimated to be 30-60 times that of the general population. A nationwide population-based case-control study performed in Sweden found an odds ratio of 7.7 for adenocarcinoma in persons with recurrent symptoms of reflux, as compared with persons without such symptoms, and an odds ratio of 43.5 in patients with long-standing and severe symptoms of reflux.[22]

Although the annual risk of developing esophageal adenocarcinoma in people with GERD has been reported at 0.5%, some studies have found lower risk. Data from the Northern Ireland Barrett Esophagus Register, which is one of the largest population-based registries in the world, found that malignant progression in patients with Barrett esophagus was 0.22% per year. This suggests that current surveillance approaches may not be cost effective.[48]

A study by Hvid-Jensen et al examined a large Danish registry (11,028 patients over a median of 5.2 years) and found the incidence of esophageal adenocarcinoma to be 1.2 cases per 1000 person-years (or 0.12% annual risk). Low-grade dysplasia detected on index endoscopy was associated with an incidence rate of 5.1 cases per 1000 person-years, compared with 1 per 1000 person-years in those without dysplasia.[49]

Additional factors that increase the risk for esophageal adenocarcinoma, particularly in patients with Barrett esophagus, include cigarette smoking[50] and certain polymorphisms of the epidermal growth factor gene that have been associated with higher serum levels of epidermal growth factor.[51] Freedman et al suggested a possible association between cholecystectomy and esophageal adenocarcinoma, likely due to the toxic effect of refluxed duodenal juice containing bile on esophageal mucosa [52]

Obesity and metabolic syndrome

Obesity has been linked to a higher risk for Barrett esophagus and esophageal adenocarcinoma.[53, 54] Individuals in the highest quartile for body mass index (BMI) have a 7.6-fold higher risk of developing esophageal adenocarcinoma compared with those in the lowest quartile. A meta-analysis of case control and cohort studies revealed a relative risk for esophageal adenocarcinoma of 1.71 (95% confidence index [CI] 1.5-1.96) for BMI between 25 and 30 kg/m2, and 2.34 (95% CI 1.95-2.81) for BMI ≥30 kg/m2.[55] Obesity does not appear to increase the risk of esophageal SCC.[56]

Obesity increases the risk of GERD and subsequently of esophageal adenocarcinoma by a "mechanical" process that consists of an amplification of intragastric pressure, disruption of normal esophageal sphincter function, and increased risk of a hiatal hernia.[57] Obesity also has an inflammatory effect mediated by the release of various proinflammatory cytokines, which can lead to metabolic syndrome, a constellation of metabolic disorders that includes obesity, impaired fasting glucose, high blood pressure, and dyslipidemia. Like obesity, metabolic syndrome is also linked with the risk of esophageal adenocarcinoma.[58]

United States statistics

The American Cancer Society estimates that 22,370 new cases of esophageal cancer (17,690 in men and 4680 in women) will be diagnosed in the United States in 2024, and that 16,130 persons (12,880 men and 3250 women) will die of the disease.[59] Esophageal cancer is the seventh most common cause of cancer death in males.[59] The 5-year survival rate from 2014 to 2020 was 21.6%.[60]

The incidence of esophageal carcinoma is approximately 3-6 cases per 100,000 population, although certain endemic areas appear to have higher per-capita rates. The age-adjusted annual incidence was 4.2 per 100,000 men and women, based on 2017-2021 cases.[60]

The epidemiology of esophageal carcinoma has changed markedly over the past several decades in the United States.[61] Until the 1970s, squamous cell carcinoma was the most common type of esophageal cancer (90-95%). It was typically located in the thoracic esophagus and most frequently affected African-American men with a long history of smoking and alcohol consumption.

Subsequently, rates of esophageal adenocarcinoma rose markedly, particularliy in Whites. In White men, the incidence rate of esophageal adenocarcinoma exceeded that of squamous cell carcinoma around 1990, while in White women aged 45–59 years, adenocarcinoma overtook squamous cell carcinoma in 2006–2010.[62]

From 1973 to 1996, the incidence of esophageal adenocarcinoma increased by 8.2% annually. From 1996 to 2006, the rate of increase fell to 1.3% annually, principally because of a plateau in the incidence of early-stage disease. Prior to 1996, early-stage cases increased by 10% annually; subsequently, they declined by 1.6% annually.[63] From 2004 to 2014, incidence rates of esophageal adenocarcinoma in the United States fell on average 1.4% each year.[60]

International statistics

Esophageal câncer is the 11th most common cancer and the 7th most common cause of cancer deaths worldwide. It is endemic in many parts of the world, particularly in the third world countries, where it is the fourth most common cause of cancer deaths. Incidence rates are variable worldwide, with the highest rates found in eastern Asia and  southern and eastern Africa, and the lowest rates in western and northern Africa and Central America in both men and women.[4]

In some regions, such as areas of northern Iran, some areas of southern Russia, and northern China (sometimes called an "esophageal cancer belt"), the incidence of esophageal carcinoma may be as high as 800 cases per 100,000 population. Major risk factors in these areas are not well known but are probably related to the poor nutritional status, including low intake of fruits and vegetables and drinking very hot beverages. Unlike in the United States, squamous cell carcinoma is responsible for 95% of all esophageal cancers worldwide.

Sex- and age-related demographics

Esophageal cancer is more common in men than in women. The male-to-female ratio is 4:1.[60]

Esophageal cancer occurs most commonly during the sixth and seventh decades of life. The disease becomes more common with advancing age; it is about 20 times more common in persons older than 65 years than it is in individuals below that age. Median age at diagnosis is 68 years.[60]

Between 2014 and 2020, the overall 5-year survival rate for esophageal cancer was 21.6%.[60] However, survival in patients with esophageal cancer depends on the stage of the disease. Squamous cell carcinoma and adenocarcinoma, stage-by-stage, appear to have equivalent survival rates.

Lymph node or solid organ metastases are associated with low survival rates. Patients without lymph node involvement have a significantly better prognosis and 5-year survival rate than patients with involved lymph nodes. Stage IV lesions with distant metastasis are associated with a 5-year survival rate of around 5%. (See the table below.)

Table 2. Five-year esophageal cancer survival rates by stage at diagnosis in the US, 2014-2020 ^[60] (Open Table in a new window)

The 5-year survival rate in 2015 was 21.5% in Whites and 13.5% in Blacks.[64]

A report of 1085 patients who underwent transhiatal esophagectomy for cancer showed that the operation was associated with a 4% operative mortality rate and a 23% 5-year survival rate. A better 5-year survival rate (48%) was identified in a subgroup of patients who had a complete response (ie, disappearance of the tumor) following preoperative radiation and chemotherapy (ie, neoadjuvant therapy).[65]

Transhiatal and transthoracic esophagectomies have equivalent long-term survival rates.[66, 67]

Imaging and prognosis

Suzuki et al found that a higher initial standardized uptake value on positron emission tomography (PET) scanning is associated with poorer overall survival in patients with esophageal or gastroesophageal carcinoma receiving chemoradiation. The authors suggested that PET scanning may become useful for individualizing therapy.[68]

A study by Gillies et al also found that PET–computed tomography (CT) scanning can be used to predict survival; in this study, the presence of fluorodeoxyglucose (FDG)-avid lymph nodes was an independent adverse prognostic factor.[69]

HER-2 and prognosis

In some studies of esophageal cancer, human epidermal growth factor 2 (HER-2) positivity correlated with tumor invasion and lymph node metastasis, and portended a poor prognosis.[10, 70] For example, a study by Prins et al of HER-2 protein overexpression and HER-2 gene amplification in esophageal carcinomas found that HER-2 positivity and gene amplification are independently associated with poor survival. In their study, which involved 154 patients with esophageal adenocarcinoma, HER-2 positivity was seen in 12% of these patients and overexpression was seen in 14% of them.[71] Current National Comprehensive Cancer Network guidelines recommend testing for HER2 and adding the HER2 monoclonal antibody  to chemotherapy regimens when HER2 overexpression is found.[10]

Dysphagia, the most common presenting symptom of esophageal cancer, is initially experienced for solids but eventually progresses to include liquids. It usually occurs when esophageal lumen diameter is under 13 mm and indicates locally advanced disease. A complaint of dysphagia in an adult should always prompt an endoscopy to help rule out the presence of esophageal cancer. A barium swallow study is also indicated in these cases.

Other symptoms include the following:

• Weight loss - This is the second most common symptom, occurring in more than 50% of people with esophageal carcinoma. It is caused by dysphagia and tumor-related anorexia. 

• Bleeding - Patients may experience bleeding from the tumor leading to iron deficiency anemia. 

• Pain - Pain may be felt in the epigastric or retrosternal area; pain over bony structures indicates metastatic disease.

• Hoarseness - This is caused by invasion of the recurrent laryngeal nerve; it is a sign that the cancer has progressed beyond the point at which surgical resection remains possible.

• Persistent cough

• Respiratory symptoms (persistent cough and recurrent pneumonia) - These can be caused by aspiration of undigested food or by direct invasion of the tracheobronchial tree by the tumor (tracheobronchial fistula); the latter is also a sign of unresectabiliy. 

Physical examination findings in patients with esophageal cancer are typically normal, unless the cancer has metastasized to neck nodes or the liver. Lymphadenopathy in the laterocervical or supraclavicular area or the presence of hepatomegaly often indicates unresectable disease.

In 2013, the Society of Thoracic Surgeons released clinical practice guidelines to assist in the diagnosis and treatment of localized esophageal cancer. Their recommendations for diagnosis include the following[72] :

• Flexible endoscopy with biopsy is the primary method for diagnosis of esophageal cancer.

• Computed tomography (CT) of the chest and abdomen is an optional test for staging of early-stage esophageal cancer, and a recommended test for staging of locoregionalized esophageal cancer.

• Positron emisison tomography (PET) is an optional test for staging of early-stage esophageal cancer, and a recommended test for staging of locoregionalized esophageal cancer.

• In patients without metastatic disease, endoscopic ultrasonography is recommended to improve the accuracy of staging

• In patients with small, discrete nodules or areas of dysplasia in whom disease appears limited to the mucosa or submucosa as assessed by endoscopic ultrasonography, endoscopic mucosal resection should be considered as a diagnostic/staging tool.

• In patients with locally advanced (T3/T4) adenocarcinoma of the esophagogastric junction infiltrating the anatomic cardia or Siewart type III esophagogastric tumors, laparoscopy is recommended to improve the accuracy of staging.

Imaging studies used in the diagnosis and staging of esophageal cancer include the following:

• CT scanning
• PET scanning
• Endoscopic ultrasound (EUS)
• Bronchoscopy
• Barium swallow

Computed tomography

Abdominal and chest computed tomography (CT) scans are useful for helping to exclude the presence of metastases (M staging) to the lungs and liver and may be useful for helping to determine whether adjacent structures have been invaded.[73] (See the image below.)

Esophageal cancer. Chest CT scan showing invasion of the trachea by esophageal cancer.

Positron emission tomography

PET scanning is also a useful baseline imaging technique and is increasingly becoming standard in the staging of esophageal cancer. It may be particularly useful in detecting occult distant lymph node metastases and bone spread. In addition, the intensity of radiopharmaceutical uptake on PET scans may reflect the biology of the cancer and thus may have prognostic significance.[68]

Endoscopic ultrasound

EUS is the most sensitive test for determining the depth of tumor penetration (T staging) and the presence of enlarged periesophageal lymph nodes (N staging).[74, 75]

Following are the characteristic features of malignant or inflammatory lymph nodes detected on EUS:

• Enlarged in size
• Hypoechoic (dark)
• Homogeneous
• Well circumscribed and rounded 

The accuracy of diagnosing nodal disease is significantly increased with the combination of above-mentioned features, but also is confirmed with the use of fine needle aspiration (FNA) biopsy for cytology assessment.[76] The combined use of EUS and FNA (EUS-FNA) has a greater accuracy than EUS alone in the evaluation of lymph node metastasis.[77] In a study that compared the role of CT, EUS, and EUS-FNA for preoperative nodal staging in 125 patients with esophageal cancer, EUS-FNA was more sensitive than CT (83% vs. 29%) and more accurate than CT (87% vs. 51%) or EUS (87% vs. 74%) for nodal staging.[78]

Patients with obstructing tumors are at increased risk for perforation during staging EUS. The risk of perforation can be reduced with the use of wire-guided or mini-EUS probes. In certain cases, the malignant stricture is dilated prior to the staging EUS.The review of CT and PET scans prior to EUS is recommended to evaluate the nodal distribution for a possible FNA biopsy.

Bronchoscopy

Bronchoscopy is indicated for cancers of the middle and upper third of the thoracic esophagus (tumor at or above carina) to help exclude invasion of the trachea or bronchi. It should be performed only if the patient shows no evidence of M1 disease. Laparoscopy and thoracoscopy have a greater than 92% accuracy in staging regional nodes.

Barium swallow

Barium swallow is very sensitive for detecting strictures (see the first image below) and intraluminal masses (see the second image below) but does not allow staging and biopsy. It is now rarely used, but it may be helpful for studying the distal anatomy in obstructive tumors that are inaccessible by endoscopy.

Esophageal cancer. Barium swallow demonstrating stricture due to cancer.

Esophageal cancer. Barium swallow demonstrating an endoluminal mass in the mid esophagus.

For more information, see the Medscape article Esophageal Carcinoma Imaging.

Esophageal cancer staging follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC).[79]

No completely satisfactory method is available to clinically stage esophageal cancer. The difficulty of clinically assessing the disease is reflected by changes over time in the AJCC staging system. The 1983 system was based on the length of the intraluminal esophageal tumor, the presence of esophageal obstruction, and the involvement of palpable lymph nodes. This clinical staging system proved to have limited value.

The 1988 revision defined a clinical and pathologic staging system based entirely on the depth of esophageal wall invasion and the presence or absence of local nodal involvement. Neither of those parameters is assessed easily on a clinical basis. Hofstetter et al therefore proposed incorporating the number of involved lymph nodes with regional and nonregional node location.[80] This modification, which seemed to be simpler and to better predict long-term survival, was adopted into the revised system.

The revised 2010 AJCC staging classification was based on the risk-adjusted random forest analysis of the data generated by the Worldwide Esophageal Cancer Collaboration (WECC) for 4627 patients who were treated with primary esophagectomy without preoperative or postoperative therapy.[81] In the data reported by the WECC, survival decreased with increasing depth of tumor invasion (T), presence of regional lymph node metastases (N), and the presence of distant metastases (M).[82]

The 2017 TNM classification for esophageal cancer is shown below (staging is detailed in Tables 2-4, below. T staging is illustrated in the image below). For more information, see Esophageal Cancer Staging.

TNM staging is as follows:

• Tis -  High-grade dysplasia (malignant cells confined to the epithelium by the basement membrane)
• T1 -   Tumor invades the lamina propria, muscularis mucosae, or submucosa
• T1a - Tumor invades the lamina propria or muscularis mucosae
• T1b - Tumor invades the submucosae
• T2 -   Tumor invades the muscularis propria
• T3 -   Tumor inades adventitia
• T4 -   Tumor invades adjacent structures
• T4a -Tumor invading into pleura, pericardium, azygos vein, diaphragm, or peritoneum
• T4b - Tumor invading other adjacent structures (eg, aorta, vertebral body, trachea)
• N0 - No regional lymph node metastasis
• N1 - 1-2 regional lymph nodes (N1 is site dependent)
• N2 - 3-6 regional lymph nodes
• N3 - More than 6 regional lymph nodes
• M0 - No distant metastasis
• M1 - Distant metastasis

Esophageal cancer. Diagram showing T1,T2 and T3 stages of esophageal cancer. Courtesy of Cancer Research UK and Wikimedia Commons.

Table 3. Clinical Staging Classification (Squamous Cell Carcinoma) (Open Table in a new window)

Table 4. Clinical Staging Classification (Adenocarcinoma) (Open Table in a new window)

All esophageal tumors, as well as tumors with epicenters within 5 cm of the esophagogastric junction that also extend into the esophagus, are classified and staged according to the AJCC/UICC esophageal scheme. Tumors with an epicenter in the stomach that are more than 5 cm from the esophagogastric junction or those within 5 cm of the esophagogastric junction without extension into the esophagus are staged using the gastric carcinoma scheme.

However, this classification may not work well for patients who have received preoperative therapy. Some other shortcomings associated with the current staging classification are as follows:

• Inclusion of proximal 5 cm of the stomach
• Lack of guidance for regional resectable and unresectable cancer
• Emphasis on the number of nodes rather than their size and anatomic locations/significance.

Other classifications—such as that of the Japanese Society for Esophageal Diseases, which is widely used in Asia—differ from that of the AJCC/UICC, especially regarding lymph node distribution and nomenclature.[83]

Laboratory studies in patients with esophageal cancer focus principally on patient factors that may affect treatment. These include complete blood count (CBC) and comprehensive metabolic panel. Nutritional status should be evaluated in patients with dysphagia; liver function studies should be performed in patients who abuse alcohol.

Upper GI endoscopy

Upper GI endoscopy allows direct visualization and biopsies of the tumor. (See the image below.)

Esophageal cancer. Endoscopy demonstrating intraluminal esophageal cancer.

Endoscopy is a very important tool in the diagnosis, staging, and surveillance of patients with esophageal cancer. Most endoscopy procedures are performed under conscious sedation. Patients who are at risk of aspiration during endoscopy may require general anesthesia. 

Diagnostic endoscopies are performed to determine the following:

• Detection of esophageal tumor
• Biopsy of any suspicious lesions
• Location of the tumor relative to the teeth and esophagogastric junction
• Tumor length
• Degree of obstruction

Esophageal tumor length, as assessed by preoperative endoscopy, has been identified as an independent predictor of long-term survival in patients with adenocarcinoma of the esophagus.[84] The 5-year survival rate was significantly higher for patients with a tumor length of 2 cm or less (78% vs 29% for those with a tumor length of more than 2 cm).

Endoscopic resection

Endoscopic resection (ER) of focal nodules should be performed in the setting of early-stage disease (T1a or T1b) to provide accurate assessment of depth of invasion, degree of differentiation, and the presence of lymphovascular invasion.[85] Thus, ER is an essential procedure for the accurate staging of early-stage cancer especially in patients with small nodular lesions (≤2 cm).[86] ER can become a therapeutic procedure if a small lesion (under 2 cm) is fully removed and histopathology reveals that the lesion is well differentiated, with penetration limited to submucosa, absence of lymphovascular invasion, and clear margins.[87]

Histologically, esophageal squamous cell carcinoma is characterized microscopically by keratinocyte-like cells with intercellular bridges or keratinization. Adenocarcinomas that arise from Barrett esophagus mucosa are typically well- or moderately differentiated and have well-formed tubular or papillary structures. In poorly differentiated adenocarcinomas, glandular structures comprise less than half of the tumor; in undifferentiated adenocarcinomas, glandular structures are absent. See the images below.

Esophageal cancer. Micrograph of squamous cell carcinoma of the esophagus (H&E stain). Courtesy of Wikimedia Commons.

Esophageal cancer. Low-magnification micrograph of an intramucosal esophageal adenocarcinoma (H&E stain). Endoscopic mucosal resection specimen. Courtesy of Wikimedia Commons.

Treatment of esophageal cancer varies according to stage—locoregional (stages I-III) versus metastatic cancer (stage IV)—and  histologic subtype—squamous cell carcinoma (SCC) versus adenocarcinoma.

National Comprehensive Cancer Network (NCCN) treatment recommendations for esophageal cancer include the following[10] :

• Endoscopic therapy (endoscopic mucosal resection, endoscopic submucosal dissection and/or ablation) is preferred for high-grade dysplasia (HGD) or T1a tumors ≤2 cm; ablation alone is a primary treatment option for patients with HGD.
• Select pT1a or pT1b tumors can be treated with endoscopic resection (ER); ablation of residual Barrett esophagus should follow ER.
• Additional ablation may be needed after ER if multifocal HGD is present elsewhere in the esophagus but may not be needed for tumors that are completely resected.
• Esophagectomy is indicated for patients with extensive HGD or pT1a adenocarcinoma with nodular disease that is not adequately controlled by ER with or without ablation; a transhiatal or transthoracic, or minimally invasive approach may be used; gastric reconstruction preferred; for postoperative nutritional support, feeding jejunostomy is preferred to gastrostomy.
• Primary treatment options for patients with SCC T1b, N+ tumors and locally advanced resectable tumors (T2-T4a, any regional N) include preoperative chemoradiation (for non-cervical esophagus tumors), definitive chemoradiation (recommended for cervical esophagus tumors) or esophagectomy (for non-cervical esophagus tumors).
• For patients with adenocarcinoma T1b, N+ tumors and locally advanced resectable tumors (T2-T4a, any regional N) preoperative chemoradiation is preferred; definitive chemoradiation is indicated only for non-surgical patients; esophagectomy is an option for patients with low-risk, < 2 cm, well-differentiated lesions.
• Tumors in the submucosa (T1b) or deeper may be treated with esophagectomy.
• For patients with SCC, no postoperative treatment is indicated if no residual disease is present at surgical margins (R0 resection).
• For patients with adenocarcinoma who have not received preoperative therapy, postoperative fluoropyrimidine-based chemoradiation (following R0 resection) is indicated for all patients with Tis, T3-T4 tumors, node-positive T1-T2 tumors, and selected patients with T2, N0 tumors with high-risk features.
• Chemotherapy following R0 resection is indicated for all patients with adenocarcinoma, irrespective of the nodal status.
• Chemoradiation may be offered to all patients with residual disease at surgical margins (R1 and R2 resections).
• Definitive chemoradiation is preferred for all T4b (unresectable) tumors.
• Fluoropyrimidine- or taxane-based regimens are indicated for preoperative and definitive chemoradiation.
• Two-drug cytotoxic regimens are preferred for patients with advanced disease because of lower toxicity.
• Trastuzumab should be added to first-line chemotherapy (category 1 for combination with cisplatin and fluoropyrimidine; category 2B for combination with other chemotherapy agents) for patients with HER2-overexpressing advanced or metastatic adenocarcinoma (a tumor immunohistochemistry [IHC] score of  3+ or 2+ with the evidence of HER2 amplification by fluorescent in situ hybridization [FISH]). ^[88]
• Ramucirumab, either as a single agent or in combination with paclitaxel, was approved in 2014 by the US Food and Drug Administration (FDA) for the treatment of patients with advanced esophagogastric junction (EGJ) adenocarcinoma refractory to or progressive following first-line therapy with platinum- or fluoropyrimidine-based chemotherapy.

Surgery remains the cornerstone of treatment for esophageal cancer. Indications for surgery include the following:

• Esophageal cancer in a patient who is a candidate for surgery

• High-grade dysplasia in a patient with Barrett esophagus that cannot be adequately treated endoscopically[2, 3]

Contraindications to surgery include the following:

• Metastasis to N2 nodes (ie, cervical or supraclavicular lymph nodes) or solid organs (eg, liver, lungs); the treatment of patients with celiac lymph node involvement remains controversial[89]

• Invasion of adjacent structures (eg, the recurrent laryngeal nerve, tracheobronchial tree, aorta, pericardium)

In addition, the presence of severe, associated comorbid conditions (eg, cardiovascular disease, respiratory disease) can decrease a patient's chances of surviving an esophageal resection. Consequently, cardiac and respiratory function must be carefully evaluated preoperatively. A forced expiratory volume in 1 second of less than 1.2 L and a left ventricular ejection fraction of less than 0.4 are relative contraindications to the operation.

Esophageal resection (esophagectomy) remains a critical component of multimodality therapy for patients with tumors of any stage. Endoscopic mucosal resection is an experimental approach to patients with T1a disease or high-grade dysplasia that is limited to certain centers and performed only under protocol. Esophagectomy is no longer is used for palliation of symptoms because other treatment modalities have become available for relieving dysphagia.

An esophagectomy can be performed by using an abdominal and a cervical incision with blunt mediastinal dissection through the esophageal hiatus (ie, transhiatal esophagectomy [THE]) or by using an abdominal and a right thoracic incision (ie, transthoracic esophagectomy [TTE]).

THE offers the advantage of avoiding a chest incision, which can cause prolonged discomfort and can further aggravate the condition of patients with compromised respiratory function. After removal of the esophagus, continuity of the gastrointestinal tract is usually reestablished using the stomach.

Some authors have questioned the validity of THE as a cancer operation because part of the operation is not performed under direct vision and fewer lymph nodes are removed than with TTE. However, many retrospective studies and 2 prospective ones have shown no difference in survival between the operations, suggesting that the factor influencing survival is not the type of operation but, rather, the stage of the cancer at the time the operation is performed.[66, 67, 90, 91, 92, 93]

Morbidity and mortality

Complications from esophagectomy occur in approximately 40% of patients. The morbidity associated with the surgery consists mostly of respiratory, cardiac, and septic complications, including the following:

• Respiratory complications (15-20%) - Include atelectasis, pleural effusion, and pneumonia

• Cardiac complications (15-20%) - Include cardiac arrhythmias and myocardial infarction

• Septic complications (10%) - Include wound infection, anastomotic leak (breakdown of the new connection between the stomach and esophagus), and pneumonia

Anastomotic leaks and stricture may require dilatation (20%). Leaks may be treated with endoscopic placement of self-expanding, removable plastic stents.[94]

Leak rates vary depending on whether the anastomosis is in the chest (3%-12%) or the neck (10%-25%).[95] The choice of location for the anastomosis is based mostly on the location of the tumor and the surgeon’s assessment of the risks and benefits of a thoracic anastomosis. Such anastomoses have a lower leak rate, but an intrathoracic leak following esophagectomy can lead to sepsis and death.

A retrospective review of 1223 esophagectomies for cancer found that surgical management of intrathoracic leaks did not increase the patient mortality rate or effect long-term survival.[95]

As with other complex operations (eg, cardiac operations, resection of the pancreas or liver), the lowest mortality rate with esophagectomy is achieved when the procedure is performed in high-volume centers by high-volume surgeons. In California from 1990-1994, for instance, 5 high-volume centers had a mortality rate of 5% or less for esophageal resection for cancer, while the state’s average mortality rate for this surgery was approximately 18%.[96]

The better results in high-volume centers are due to a team approach. In these facilities, expert surgeons work with intensivists, cardiologists, pulmonologists, radiologists, and nurses who have experience and expertise.

Transthoracic esophagectomy

There are two types of TTE, as follows:

• Ivor Lewis esophagectomy (right thoracotomy and laparotomy)
• McKeown esophagectomy (right thoracotomy followed by laparotomy and cervical anastomosis) 

For TTE, the patient is placed supine on the operating room table. An arterial line, a central venous catheter, a Foley catheter, and a dual-lumen endotracheal tube are placed. Preoperative antibiotics are administered. An upper midline incision is made.

After exploring the peritoneal cavity for metastatic disease (if metastases are found, the operation is not continued), the stomach is mobilized. The right gastric and the right gastroepiploic arteries are preserved, while the short gastric vessels and the left gastric artery are divided.

Next, the gastroesophageal junction is mobilized, and the esophageal hiatus is enlarged. A pyloromyotomy is performed, and a feeding jejunostomy is placed for postoperative nutritional support.

After closure of the abdominal incision, the patient is repositioned in the left lateral decubitus position and a right posterolateral thoracotomy is performed in the fifth intercostal space.

The azygos vein is divided to allow full mobilization of the esophagus. The stomach is delivered into the chest through the hiatus and is then divided approximately 5 cm below the gastroesophageal junction.

An anastomosis (hand-sewn or stapled) is performed between the esophagus and the stomach at the apex of the right chest cavity. Then, the chest incision is closed.

McKeown esophagectomy, with an anastomosis in the cervical region, is similar in conduct, but with the advantage of being applicable for tumors in the upper, middle, and lower thoracic esophagus.

Transhiatal esophagectomy

For THE, the preoperative details are similar to those of TTE, except that a single-lumen, rather than a double-lumen, endotracheal tube is used. The neck is prepared in the operative field.

The abdominal part of the operation is identical to the TTE; however, dissection of the esophagus is performed through the enlarged esophageal hiatus without opening the right chest. The esophagus is mobilized in this fashion all the way to the thoracic inlet.

Then, a 6-cm incision is made in the left side of the neck. The internal jugular vein and carotid artery are retracted laterally, and the esophagus is identified and isolated posterior to the airway. To prevent injury to the left recurrent laryngeal nerve, no mechanical retractors are used to retract the trachea.

Next, after resection of the proximal stomach and thoracic esophagus, the remaining stomach is pulled up through the posterior mediastinum until it reaches the remaining esophagus at the cervical level. Then, a hand-sewn anastomosis is performed, and a small drain is placed in the neck alongside the anastomosis. The abdominal and neck incisions are closed. (See the image below.)

Esophageal cancer. Transhiatal esophagectomy in which (a) is the abdominal incision, (b) is the cervical incision, and (c) is the stomach stretching from abdomen to the neck.

Minimally invasive esophagectomy

The use of laparoscopic and thoracoscopic techniques has revolutionized the treatment of benign esophageal disorders such as achalasia and gastroesophageal reflux disease (GERD). Advantages of minimally invasive surgery include a shorter hospital stay, less postoperative discomfort, and much faster recovery time than with open surgery. Minimally invasive esophagectomy (MIE) is finding a place in the treatment of esophageal cancer.[97]

In a study of MIE (mainly using thoracoscopic mobilization) in 222 patients, the mortality rate was only 1.4% and hospital stay was only 7 days, which is less than with most open procedures; only 16 patients (7.2%) required conversion to an open procedure.[98] A report by Luketich et al involving 56 patients also showed that MIE was comparable to open esophagectomy but the use of neoadjuvant treatment slightly increased the surgical mortality from 1.5% to 1.8%.[98]

In a randomized French study that compared transthoracic open esophagectomy (n=104) with MIE (hybrid procedure; n=103), .Mariette et al reported that the incidence of intraoperative and postoperative major complications, specifically pulmonary complications, was 69% lower with the hybrid procedure, while 3- and 5-year overall survival and disease-free survival were noninferior. For the hybrid procedure, the abdominal portion of the operation was performed through five small incisions, rather than the long abdominal incision used in TTE.[99]

Video-assisted thoracoscopy (VATS) is being used in many centers for the thoracic mobilization of the esophagus, reducing the size of the chest incision. In addition, laparoscopy can be used to mobilize the gastric conduit in the abdomen, reducing abdominal incision size as well.

A study by Uenosono et al found that sentinel node mapping can be applied to patients with clinical T1 and N0 esophageal cancer. Use of this technique may facilitate less invasive surgery, with reduction of lymphadenectomy.[100]

Endoscopic mucosal resection (EMR) is a modern, attractive option for the treatment of superficial esophageal cancers. High-grade dysplasia and mucosa-limited neoplasms are candidates for EMR, because of the low risk of node metastasis in these cases. A population-based study of 1618 patients with grade Tis, T1a, or T1b esophageal cancer found that overall survival times and esophageal-cancer-specific survival times with endoscopic therapy were similar to those with surgery, after adjustment for patient and tumor factors.[101, 102]

Salvage endoscopic resection

In patients with local failure after definitive chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (SCC), salvage endoscopic treatment (SET) may be a viable option, according to a study reported at the 2014 Gastrointestinal Cancers Symposium.[103] The study included 716 esophageal SCC patients treated with CRT, 417 of whom experienced local failure (incomplete response or local recurrence); of these 417 patients, 164 underwent SET (either photodynamic therapy or endoscopic resection).

Curative resection was achieved in 88% of the patients who underwent endoscopic resection, and a complete response was achieved in 57.5% of those who underwent photodynamic therapy.[103] Overall survival and relapse-free survival rates at 5 years were 38.6% and 28%, respectively. The factors most strongly predictive of improved survival were (1) an absence of lymph node metastasis before CRT and (2) an elapsed time of 6 months or longer between the initiation of CRT and the performance of SET.[103]

Chemotherapy and radiotherapy for esophageal cancer are delivered preoperatively. No survival benefit is obtained when radiation and chemotherapy are administered postoperatively; however, postoperative continuance of chemotherapy started preoperatively may be beneficial.[104] The aims of preoperative (neoadjuvant) chemotherapy and radiotherapy are to reduce the bulk of the primary tumor before surgery to facilitate higher curative resection rates and to eliminate or delay the appearance of distant metastases.

Most chemotherapy agents that are currently used for the treatment of esophageal cancer, including alkylating, antimetabolite, anthracycline, and antimicrotubular agents, are not approved for this indication by the US Food and Drug Administration (FDA). Chemotherapy for squamous cell esophageal carcinoma, as with squamous cell carcinomas in general, is based on cisplatin, while chemotherapy for esophageal adenocarcinoma has been extrapolated from experience in patients with adenocarcinoma of the stomach.

Neoadjuvant chemotherapy alone appears to offer a limited benefit at best. A North American randomized trial found that preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with squamous cell cancer or adenocarcinoma of the esophagus. In a larger trial, British investigators found that preoperative chemotherapy with those 2 agents resulted in a 5-year survival rate of 23.0%, compared with 17.1% for surgery alone.[105]

In contrast, the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) demonstrated considerable benefit from preoperative chemoradiation over surgery alone in selected patients with esophageal or esophagogastric junction (EGJ) cancer (tumor stage T1N1 or T2–T3 with any N).[106] Median overall survival with chemoradiation therapy followed by surgery was 49.4 months, compared with 24.0 months with surgery alone.

An analysis of data from CROSS I and II showed that preoperative chemoradiotherapy (CRT) plus surgery was superior to surgery alone in preventing local, regional, and distant recurrence, particularly hematogenous metastasis and peritoneal carcinomatosis.[107, 108] Overall recurrence rates were 35% for CRT plus surgery and 58% for surgery alone. The rates of locoregional recurrence, peritoneal carcinomatosis, and hematogenous dissemination were all lower for the former as well (14% vs 34%, 4% vs 14%, and 29% vs 35%, respectively).

Neoadjuvant therapy consists of a combination of radiotherapy (approximately 45 Gy) and chemotherapy with cisplatin and 5-fluorouracil. While the radiotherapy acts locally at the tumor site, the chemotherapy acts on tumor cells that have already spread. This combination therapy is usually administered over a 45-day period; esophageal resection is performed after an interval of approximately 4 weeks.

In a study of patients with distal esophageal carcinoma, Franko and colleagues reported that a longer interval between neoadjuvant chemoradiation and esophagectomy was significantly associated with worse outcomes. The median interval between radiation therapy and esophagectomy was 7.1 weeks; when the delay was 9 weeks or more, perioperative mortality was increased and overall survival decreased.[109]

Rohatgi et al reported that the response to preoperative chemoradiotherapy correlated strongly with overall survival and disease-free survival in patients with esophageal cancer. In their review of 235 cases, survival decreased progressively between patients who achieved a pathologic complete response, those who had a partial response (1-50% residual carcinoma in the resected specimen), and those with no response (greater than 50% residual carcinoma).[110]

A trial involving 111 patients undergoing chemoradiotherapy for head-and-neck or esophageal cancer indicated that enteral nutrition enriched with n-3 fatty acids helps to preserve body mass and improve nutritional and functional status parameters during chemoradiotherapy.[111]  

PD-L1 inhibitors

Pembrolizumab

In 2019, the FDA approved pembrolizumab (Keytruda) for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus whose tumors express programmed death ligand 1 (PD-L1) with a Combined Positive Score (CPS) ≥10, as determined by an FDA-approved test, with disease progression after 1 or more prior lines of systemic therapy.[112]

Efficacy was observed in two clinical trials, KEYNOTE‑181 and KEYNOTE‑180. KEYNOTE-181 (n=628) was a phase 3 randomized, open-label, active-controlled trial that enrolled patients with recurrent locally advanced or metastatic esophageal cancer that had progressed on or after one prior line of systemic treatment for advanced or metastatic disease. Patients were randomized to receive either pembrolizumab or the investigator’s choice of a paclitaxel, docetaxel, or irinotecan regimen as a control arm. In patients with PD-L1 CPS ≥10, the median overall survival was 9.3 months in the pembrolizumab arm and and 6.7 months in the control arm.[113]

KEYNOTE‑180 was a single arm, open-label trial that enrolled patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. Clinically meaningful therapeutic activity was observed regardless of tumor histology, although the objective response rate was higher in patients with squamous cell carcinoma than in those with adenocarcinoma (14.3% versus 5.2%) and in patients with PD-L1–positive tumors than in those with PD-L1–negative tumors (13.8% versus 6.3%). Response durations ranged from 4.2 to 25.1+ months, with 71% of patients having responses of 6 months or longer and 57% having responses of 12 months or longer.[114]

In 2021, the FDA granted accelerated approval to pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Approval was based on the KEYNOTE-811 trial, a multicenter, randomized, double-blind, placebo-controlled trial in patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. The overall response rate was 74% (95% CI 66, 82) in the pembrolizumab arm and 52% (95% CI 43, 61) in the placebo arm. The median duration of response was 10.6 months for the pembrolizumab arm and 9.5 months for the placebo arm.[115]  

Nivolumab

The FDA approved nivolumab in 2021 for first-line immunotherapy in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic esophageal adenocarcinoma and GEJ cancer, as well as for gastric cancer. In the phase 3 CheckMate 649 trial, which involved 1581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ cancer, or esophageal adenocarcinoma, 60% of which had a PD-L1 CPS ≥5, nivolumab plus oxaliplatin-based chemotherapy was associated with significantly better overall survival (OS) than chemotherapy alone (13.8 months vs 11.6 months, respectively; P = 0.0002). In patients with a PD-L1 CPS ≥5, progression-free survival (PFS) was also significantly improved with nivolumab plus chemotherapy (median 7.7 months vs 6.0 months, P < 0.0001).[116]

In the phase 3 ATTRACTION-4 study, conducted in Japan, Korea, and Taiwan, which involved involved 724 previously untreated patients with HER2-negative gastric or GEJ cancer, nivolumab plus chemotherapy did not significantly improve OS but did significantly improve PFS, at a median 10.5 months vs 8.3 months with chemotherapy alone (P = 0.0007).[117]

Despite these findings, the FDA approved nivolumab for completely resected esophageal or GEJ cancer in patients with residual pathologic disease who have received neoadjuvant chemoradiotherapy. Approval was based on the randomized, double-blind CHECKMATE-577 trial in 794 patients with completely resected esophageal or GEJ cancers who had residual pathologic disease following concurrent chemoradiotherapy. A statistically significant improvement in disease-free survival (DFS) was demonstrated in the nivolumab arm compared with the placebo arm (22.4 vs 11 months, respectively). The DFS benefit was observed regardless of tumor PD-L1 expression and histology.[118]

In 2022, the FDA issued two approvals of nivolumab for the first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma, based on results of the CHECKMATE-648 trial[119] :

• Nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy
• Nivolumab in combination with ipilimumab

Tislelizumab 

The FDA approved tislelizumab (Tevimbra) in March 2024 for adults with unresectable or metastatic esophageal squamous cell carcinoma after prior systemic chemotherapy that did not include a PD-L1 inhibitor. Tislelizumab n is an IgG4 anti-PD1 monoclonal antibody.[120]

Approval was supported by evidence from the global phase 3 RATIONALE-302 trial. Results showed a significant improvement in overall survival with tislelizumab compared with chemotherapy (8.6 versus 6.3 months, respectively). A higher objective response rate and a more durable antitumor response ( 7.1 vs 4.0 months, respectively) was also observed.[121]

The FDA is also reviewing tisleizumab as a first-line therapy for unresectable, recurrent, locally advanced, or metastatic esophageal or gastroesophageal carcinoma.

Other chemotherapy

Tipiracil/trifluridine

The FDA approved tipiracil/trifluridine in 2019 for metastatic gastric or GEJ adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

Approval of tipiracil/trifluridine was based on the phase 3 TAGS (TAS-102 Gastric Study) clinical trial (n=507). Patients in the tipiracil/trifluridine group had a median overall survival 5.7 months compared with 3.6 months in the placebo group (one-sided P=0.00029, two-sided P=0.00058).[122]

Ramucirumab/paclitaxel

Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that is indicated for use as a single agent or in combination with paclitaxel for advanced gastro-esophageal junction adenocarcinoma in patients with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. In the phase 3 RAINBOW trial, overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9.6 months vs 7.4 months, respectively).[123]

In patients who are not candidates for surgery, because of their clinical condition or advanced disease, treatment focuses on control of dysphagia. The goal of palliative care is to prevent and relieve suffering and improve quality of life for patients and their caregivers regardless of the disease stage. In patients with unresectable or locally advanced cancer, palliative interventions provide symptomatic relief and may result in significant prolongation of life, improvement in nutritional status, the sensation of well-being, and overall quality of life.

Although various treatment options are available for the management of dysphagia, optimal treatment is still debated. A multimodality interdisciplinary approach is strongly encouraged.

Dysphagia is the most common symptom in patients with esophageal cancer. Assessing the severity of the condition and swallowing impairment is essential to initiate appropriate interventions for long-term palliation of dysphagia in patients with esophageal cancer.

Available palliative methods for the management of dysphagia include the following:

• Endoscopic lumen restoration or enhancement
• Temporary self-expanding metal stents (SEMS)
• External beam radiation therapy (EBRT) 
• Brachytherapy
• Chemotherapy
• Laser
• Surgery

National Comprehensive Cancer Network guidelines for best supportive/palliative care

For patients with complete esophageal obstruction, the NCCN guidelines[10] recommend the following:

• Endoscopic lumen restoration
• EBRT
• Chemotherapy
• Surgery

Surgical or radiologic placement of jejunostomy or gastronomy tubes may be necessary to provide adequate hydration and nutrition, if endoscopic lumen restoration is not undertaken or is unsuccessful. Brachytherapy may be considered instead of EBRT if lumen can be restored using appropriate applicators during the delivery of brachytherapy to avoid an excessive dose on mucosal surfaces. In a multicenter randomized trial, single-dose brachytherapy was associated with fewer complications and better long-term relief of dysphagia compared with metal stents.[124]  

For patients with severe esophageal obstruction (those able to swallow liquids only), some additional options include endoscopic lumen enhancement (wire-guided or balloon dilation) and endoscopy or fluoroscopy-guided placement of covered expandable metal stents. While some data suggest a lower migration and re-obstruction rate with the larger-diameter covered expandable metal stents, there may be a higher risk of stent-related complications[125]  

Stents

Long-term palliation of dysphagia can be achieved with endoscopic, radiographic-assisted insertion of expandable metal or plastic stents.[126, 127] Temporary placement of self-expanding metal stents (SEMS) with concurrent EBRT was found to increase survival rates compared with permanent stent placement.[128] SEMS is the preferred treatment for patients with tracheoesophageal fistula and those who are not candidates for chemoradiation or who failed to achieve adequate palliation with such therapy.[129] Membrane-covered stents have significantly better palliation than conventional bare metal stents because of a lower rate of tumor ingrowth.[127]

Radiotherapy

Radiation therapy is successful in relieving dysphagia in approximately 50% of patients. In patients with advanced esophageal cancer, the preoperative combination of chemotherapy and radiotherapy has shown good results.

In a large, multicenter study, Herskovic and colleagues reported a 2-year survival rate of 38%, with a median survival period of 12.5 months, for patients treated with radiotherapy in combination with chemotherapy (fluorouracil and cisplatin), compared with a 2-year-survival rate of 10% and a median survival period of 8.5 months in patients treated with radiotherapy alone.[130, 131]

Folkert et al found that high-dose-rate (HDR) endoluminal brachytherapy was well tolerated in medically inoperable patients with superficial primary or recurrent esophageal cancer. Over the course of 3 years, 14 patients were treated with HDR intraluminal brachytherapy; 10 had recurrent esophageal cancer and 4 had previously unirradiated lesions. The overall freedom from failure (OFFF) and the overall survival (OS) rate at 18 months were 30.8% and 72.7%, respectively. Patients with recurrent disease had an 11.1% OFFF and a 55.6% OS rate at 18 months. For patients with previously unirradiated disease, the OFFF was 75% and the OS rate was 100%.[132]

Chemotherapy

Chemotherapy as a single modality has limited use. Only a few patients achieve a modest and short-lived response.

A phase 3 study from the United Kingdom suggests that docetaxel may be useful as a second-line treatment for patients with esophageal cancer who have progressed after first-line chemotherapy.[133] Median overall survival was significantly better in patients treated with docetaxel than in those managed with active symptom control (5.2 versus 3.6 months, respectively).

Because survival in these patients is measured in months, quality of life is an important consideration. In the UK study, quality-of-life questionnaires demonstrated no differences between the 2 groups on global and functioning scores but did indicate an improvement in symptom scores, with the docetaxel group reporting less pain.[133]

In 2006, a Cochrane review tried to assess the effectiveness of chemotherapy versus best supportive care, as well as that of different chemotherapy regimens against each other, in metastatic esophageal carcinoma. The authors found that no consistent benefit with any specific chemotherapy regimen.[134] Cisplatin, 5-fluorouracil (5-FU), paclitaxel, and anthracyclines had promising response rates and tolerable toxicity.

Laser therapy

Laser therapy (Nd:YAG laser) can help to achieve temporary relief of dysphagia in as many as 70% of patients. Multiple sessions are usually required to keep the esophageal lumen patent.

The photosensitizer porfimer (Photofrin) is FDA approved for palliation of patients with completely obstructing esophageal cancer or partially obstructing cancer that cannot be satisfactorily treated with Nd:YAG laser therapy. Intravenous injection of porfimer is followed 40–50 hours later with delivery of 630 nm wavelength laser light; a second laser light treatment may be given 96–120 hours after the injection. Photodynamic therapy (PDT) with porfimer sodium has overall equal efficacy to Nd:YAG laser thermal ablation for palliation of dysphagia in esophageal cancer, and equal or better objective tumor response rate. Temporary photosensitivity is a limitation, but PDT is carried out with greater ease and is associated with fewer acute perforations than Nd:YAG laser therapy[126] .

The average length of postoperative hospital stay for patients with esophageal cancer is 9-14 days. Patients usually spend the first postoperative night in the intensive care unit (ICU).

Patients can be extubated immediately after the operation, but mechanical ventilation should be continued if any concerns about the respiratory status are present. Respiratory complications (eg, atelectasis, pleural effusion, pneumonia) and cardiac complications (eg, cardiac arrhythmias) usually occur in the first postoperative days. Patients leave the ICU and are transferred to the surgical ward only when their respiratory status and cardiac status are satisfactory.

Feeding through the feeding jejunostomy begins on postoperative day 1. On postoperative day 6, a swallow study is performed to check for anastomotic leakage. If no leak is present, patients start oral feedings. If a leak is present, the drainage tubes are left in place and nutrition is provided entirely through the feeding jejunostomy until the leak closes spontaneously.

Approximately 85%-90% of patients go home after discharge. The remaining patients may need additional time in a skilled nursing facility if they live alone and if they cannot take care of themselves.

Patients are seen by the responsible surgeon at 2 weeks and 4 weeks after discharge from the hospital and subsequently every 6 months by an oncologist. Most patients return to their regular level of activities within 2 months.

For squamous cell carcinoma, prevention consists of smoking cessation, efforts to reduce alcohol abuse, and consumption of a diet containing an adequate amount of fruits, vegetables, and vitamins. Both the National Comprehensive Cancer Network (NCCN) guidelines and the National Cancer Institute (NCI) cancer information summary for esophageal cancer prevention conclude that smoking cessation decreases the risk of squamous cell carcinoma.[10, 135]

For esophageal adenocarcinoma, prevention involves stopping the sequence of events leading from gastroesophageal reflux disease (GERD) to Barrett esophagus to adenocarcinoma. Better control of gastroesophageal reflux can prevent the development of Barrett metaplasia in patients with GERD and can discourage the development of high-grade dysplasia in patients with metaplasia. Endoscopic follow-up evaluations should be performed at 1- to 2-year interval to detect the presence of dysplasia, allowing intervention before cancer develops

Hereditary Cancer Predisposition Syndromes Associated with an Increased Risk for Esophageal and EGJ Cancers

Surveillance upper endoscopy with biopsy (see the table below) should be considered for patients who have one of the following hereditary cancer predisposition syndromes:

• Tylosis (non-epidermolytic palmoplantar keratosis [PPK] or Howel Evans Syndrome)
• Familial Barrett esophagus (FBE)
• Bloom syndrome
• Fanconi anemia (FA)

Table 5. Hereditary Cancer Predisposition Syndromes Associated with an Increased Risk for Esophageal Cancers. (Open Table in a new window)

Guidelines on the following aspects of esophageal cancer management have been published, by multiple groups:

• Screening and surveillance ^{[143, 144, 11, 145]}
• Diagnosis ^{[72, 10, 12, 146]}
• Management of esophageal adenocarcinoma ^{[10, 11, 12, 13]}
• Management of squamous cell carcinoma ^{[10, 12]}
• Follow-up ^{[10, 12]}
• Palliative care ^{[10, 12]}

For more information on this topic, see Esophageal Cancer Guidelines.

Most of the chemotherapy agents currently used for the treatment of esophageal cancer have not been approved by the US Food and Drug Administration (FDA) for this specific indication. Drug classes used in these regimens include alkylating, antimetabolite, anthracycline, and antimicrotubular agents. However, several biologic agents, such as programmed death ligand 1 (PD-L1) inhibitors have received FDA approval for use in esophageal cancer, and trastuzumab has been approved for use in esophagogastric junction adenocarcinoma that overexpresses HER2.

Class Summary

These agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.

Fluorouracil (Adrucil)

Fluorouracil is a pyrimidine antimetabolite. Several mechanisms of action have been proposed, including inhibition of thymidylate synthase and inhibition of RNA synthesis. This agent is also a potent radiosensitizer.

Capecitabine (Xeloda)

Capecitabine is a pyrimidine antimetabolite and a prodrug of fluorouracil. It forms the active moiety, fluorouracil, by undergoing hydrolysis in the liver and tissues. Capecitabine is used for the treatment of esophageal cancer, which is an off-label indication.

Class Summary

These agents inhibit cell growth and proliferation, interfering with DNA synthesis by the formation of DNA cross-links. Alkylating agents can have serious adverse effects such as bone marrow suppression, anaphylactic-like reactions, ototoxicity, renal toxicity, and vomiting.

Cisplatin

Intrastrand cross-linking of DNA and inhibition of DNA precursors are among the proposed mechanisms of action for cisplatin. This agent is used in combination with radiation therapy. Cisplatin has black box warnings for adverse reactions, including anaphylactic-like reactions, ototoxicity, and renal toxicity.

Carboplatin

Carboplatin is a platinum alkylating agent that interferes with the function of DNA by producing interstrand DNA cross-links. It can be used in combination with paclitaxel for the treatment of esophageal cancer, which is an off-label indication. Carboplatin has black box warnings including bone marrow suppression, anaphylactic reactions, and vomiting.

Oxaliplatin (Eloxatin)

Oxaliplatin is a platinum alkylating agent that inhibits DNA replication and transcription, resulting in cell death. It can be used in combination chemotherapy for the treatment of esophageal cancer, which is an off-label indication. It has a black box warning for anaphylactic reactions, which can be managed with epinephrine, corticosteroids, and antihistamines.

Class Summary

PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound.

Nivolumab (Opdivo)

Indicated in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. 

Pembrolizumab (Keytruda)

Indicated in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma that is not amenable to surgical resection or definitive chemoradiation. Also indicated as a single agent for recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express programmed death ligand 1 (PD-L1) with a Combined Positive Score (CPS) 10 or greater, as determined by an FDA-approved test, with disease progression after 1 or more prior lines of systemic therapy. 

Tislelizumab (Tevimbra)

Indicated for unresectable or metastatic esophageal squamous cell carcinoma (ESCC) in patients previously treated with systemic chemotherapy that did not include a PD-L1 inhibitor. 

Class Summary

These agents prevent cell growth and proliferation. They work by enhancing tubulin dimers, stabilizing existing microtubules, and inhibiting microtubule disassembly.

Docetaxel (Taxotere, Docefrez)

Docetaxel inhibits the depolymerization of tubulin, which inhibits DNA, RNA, and protein synthesis. It can be used in combination with cisplatin and fluorouracil for the treatment of esophageal cancer, which is an off-label indication. It has several black box warnings such as bone marrow suppression, fluid retention, and hypersensitivity reactions.

Use of docetaxel is not recommended in certain patients with hepatic impairment. Patients receiving treatment with docetaxel should be premedicated with corticosteroids the day before administration to help reduce fluid retention and hypersensitivity reactions.

Paclitaxel

Paclitaxel promotes microtubule assembly, interferes with the G2 mitotic phase, and inhibits cell replication. Although not FDA approved, it has been used in combination chemotherapy for the treatment of esophageal cancer. Paclitaxel has an orphan drug indication for the treatment of adenocarcinoma. Black box warnings for this drug include bone marrow suppression and hypersensitivity reactions.

Class Summary

Anthracycline antineoplastics inhibit DNA and RNA synthesis by steric obstruction. They intercalate between DNA base pairs and trigger DNA cleavage by topoisomerase II.

Epirubicin (Ellence)

Epirubicin inhibits DNA and RNA synthesis. It can be used off label as part of a combination chemotherapy regimen for the treatment of esophageal cancer. It has several black box warnings, including bone marrow suppression, extravasation, myocardial toxicity, and secondary malignancy. Dosage reduction is recommended in patients with mild to moderate hepatic impairment.

Class Summary

These agents prevent cell growth and proliferation. They work by binding to topoisomerase and causing single-strand DNA breaks.

Irinotecan (Camptosar)

Irinotecan binds reversibly to the topoisomerase I–DNA complex and prevents the ligation of the cleaved DNA strand. It can be used as part of combination chemotherapy for the treatment of esophageal cancer, which is an off-label indication. Black box warnings for irinotecan include bone marrow suppression and diarrhea.

Class Summary

Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation.

Tipiracil/trifluridine (Lonsurf)

Tipiracil is a thymidine phosphorylase inhibitor that increases trifluridine exposure by inhibiting its metabolism. Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA, interferes with DNA synthesis, and inhibits cell proliferation. It is indicated for metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

Class Summary

This category includes miscellaneous antineoplastic agents that cause cytotoxic activity by various mechanisms of action.

Porfimer (Photofrin)

Porfimer is a photodynamic therapy that causes cytotoxic activity by producing oxygen free-radicals in the presence of laser light. It also can release thromboxane A2, leading to necrosis and vascular occlusion. It is indicated for palliation in patients with partially or completely obstructing esophageal cancer.

Trastuzumab (Herceptin, Herzuma, Kanjinti)

Monoclonal antibody, inhibits growth of tumor cells that overexpress HER2

Ramucirumab (Cyramza)

Vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. Indicated for use as a single agent or in combination with paclitaxel for advanced gastro-esophageal junction adenocarcinoma in patients with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.